Sex-dependent treatment of chronic EAE with partial MHC class II constructs.
Sex-dependent treatment of chronic EAE with partial MHC class II constructs.
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DOI：
10.1186/s12974-017-0873-y
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发表时间：
2017-05-06
影响因子：
9.3
通讯作者：
Vandenbark AA
中科院分区：
文献类型：
--
作者：
Benedek G;Chaudhary P;Meza-Romero R;Calkins E;Kent G;Offner H;Bourdette D;Vandenbark AA
治疗多发性硬化（MS）的主要挑战之一是逆转进展性MS受试者的中枢神经系统（CNS）中累积损伤的作用。虽然大多数可用于MS受试者的药物是抗炎的，因此仅限于复发缓解型MS受试者，但尚不清楚它们的作用能够在何种程度上诱导患有慢性MS的受试者的轴突修复和髓鞘再生。使用实验性自身免疫性脑脊髓炎（EAE）的慢性模型来评估部分MHC（pMHC）II类构建体在治疗进行性EAE中的效力。我们证明了雌激素受体α（ERα）依赖性增加的剂量要求，以有效治疗雌性与雄性小鼠使用pMHC。使用100 μg剂量的RTL 342 M或DRα1-mMOG-35-55构建体的这种治疗显著逆转了临床严重程度，并显示出抑制雄性小鼠中持续CNS损伤、脱髓鞘和炎性细胞浸润到CNS中的明显趋势。相比之下，WT雌性小鼠需要更大的1 mg剂量才能有效治疗，尽管较低的100 μg剂量在卵巢切除或ERα缺陷的EAE小鼠中有效。这些发现将有助于设计未来的临床试验使用pMHC治疗进行性MS.在线版本的这篇文章（doi：10.1186/s12974-017-0873-y）包含补充材料，这是提供给授权用户。
One of the main challenges in treating multiple sclerosis (MS) is reversing the effects of accumulated damage in the central nervous system (CNS) of progressive MS subjects. While most of the available drugs for MS subjects are anti-inflammatory and thus are limited to relapsing-remitting MS subjects, it is not clear to what extent their effects are capable of inducing axonal repair and remyelination in subjects with chronic MS. A chronic model of experimental autoimmune encephalomyelitis (EAE) was used to evaluate the potency of partial MHC (pMHC) class II constructs in treating progressive EAE. We demonstrated an estrogen receptor alpha (ERα)-dependent increased dose requirement for effective treatment of female vs. male mice using pMHC. Such treatment using 100-μg doses of RTL342M or DRα1-mMOG-35-55 constructs significantly reversed clinical severity and showed a clear trend for inhibiting ongoing CNS damage, demyelination, and infiltration of inflammatory cells into the CNS in male mice. In contrast, WT female mice required larger 1-mg doses for effective treatment, although lower 100-μg doses were effective in ovariectomized or ERα-deficient mice with EAE. These findings will assist in the design of future clinical trials using pMHC for treatment of progressive MS. The online version of this article (doi:10.1186/s12974-017-0873-y) contains supplementary material, which is available to authorized users.